Correspondence

The Diversity of T Cells

N Engl J Med 2001; 344:231-232January 18, 2001

Article

To the Editor:

The excellent review by von Andrian and Mackay (Oct. 5 issue)1 outlines the challenges faced by the lymphoid system when it responds to a diverse array of pathogens. In their introduction the authors restate a common misconception about the magnitude of the T-cell response to individual pathogens, noting that “the number of cells whose T-cell receptors recognize any individual antigen is very limited (several thousand at most).” Historical estimates of the frequencies of precursor T cells specific for recall antigens (e.g., in influenza), derived primarily from limiting-dilution assays and analogous techniques, have been consistent with such an estimate.

These estimates are in sharp contrast to the estimated frequency of antigen-specific T cells in the setting of certain human and murine viral infections. With the use of cytokine flow-cytometric studies to evaluate functional CD4+ T-cell responses, the frequencies of cytomegalovirus-specific cells in healthy subjects and in patients infected with the human immunodeficiency virus type 1 (HIV-1) have been found to range from 1 in 100 to 1 in 10 CD4+ T cells, even in the absence of detectable viremia.2 Likewise, analysis of the T-cell response to Epstein–Barr virus in humans 3 and of the T-cell response to lymphocytic choriomeningitis virus in mice,4 in studies using major-histocompatibility-complex (MHC) class I tetramers to enumerate antigen-specific CD8+ T cells, showed that the frequencies of antigen-specific T cells were as high as 40 percent of peripheral-blood CD8+ cells in the setting of acute infection. High frequencies of antigen-specific CD8+ memory T cells (>1 in 100) have also been reported during chronic infection with these viruses. On the basis of these estimates, the total number of T cells that respond to human herpesvirus may well be more than several million, rather than several thousand, as von Andrian and Mackay suggest.

The authors ask, how is it that a relatively small number of antigen-specific T cells can locate and eliminate remotely scattered targets over a broad territory? Their question is no less important in the light of these revised estimates. Another challenge facing those studying T-cell immunity is to understand why memory T cells specific for other viruses (e.g., HIV-1) and cancers appear to be much more rare than those that respond to cytomegalovirus and Epstein–Barr virus. An answer to this question may provide insights into both the pathogenesis of these diseases and the use of vaccines to prevent them.

Krishna V. Komanduri, M.D.
University of Texas M.D. Anderson Cancer Center, Houston, TX 77030

Joseph M. McCune, M.D., Ph.D.
University of California, San Francisco, San Francisco, CA 94103

4 References

1. 1

   von Andrian UH, Mackay CR. T-cell function and migration: two sides of the same coin. N Engl J Med 2000;343:1020-1034
   Full Text | Web of Science | Medline

2. 2

   Komanduri KV, Viswanathan MN, Wieder ED, et al. Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med 1998;4:953-956
   CrossRef | Web of Science | Medline

3. 3

   Murali-Krishna K, Altman JD, Suresh M, et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 1998;8:177-187
   CrossRef | Web of Science | Medline

4. 4

   Callan MFC, Tan L, Annels N, et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J Exp Med 1998;187:1395-1402
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Komanduri and McCune comment on a statement we made in discussing the diversity of “T cells that have never encountered antigen, referred to as naive T cells.” We arrived at the number of such cells that bear any particular T-cell receptor on the basis of the estimate that about half the 5×10¹¹ lymphocytes in adults are T cells.1 About 70 percent are naive, but this fraction is much smaller in older persons. The most common T-cell receptor, consisting of α/β chains, is found on approximately 90 percent of all T cells. Thus, we estimate that the naive α/β T-cell pool in adults contains approximately 1.5×10¹¹ cells. There are at least 25×10⁶ different α/β T-cell receptors on naive T cells in human peripheral blood.2 On average, this amounts to 6000 naive T cells at most for each α/β T-cell receptor. Although the size of individual clones may vary, the number of cells that actively recirculate at any point in time may be smaller, since 98 percent of all lymphocytes are sequestered in tissues.1 Studies using MHC tetramers and T-cell–receptor sequencing in nonimmune mice have shown that the upper limit for the number of T-cell precursors in the spleen is 200,3 a finding that is consistent with our estimate in humans.

Komanduri and McCune correctly point out that the frequency of antigen-reactive T cells increases dramatically during and after viral infections. Indeed, clonal expansion of antigen-primed T cells is a fundamental tenet of immunity and immunologic memory. This concept is entirely consistent with one of the central points in our review — that T-cell migration changes after antigen priming. T-cell expansion is accompanied by differentiation into effector and memory cells and the adoption of new pathways for migration and positioning, allowing for immunologic protection at sites such as epithelial surfaces, where pathogens are first encountered. Epithelial tissues cover an enormous surface area, which cannot be efficiently surveyed by small numbers of antigen-specific lymphocytes in the pool of naive T cells; this feat can be accomplished only with a greatly increased frequency of antigen-specific T cells, such as the frequencies noted by Komanduri and McCune. As they point out, the degree of clonal expansion can vary, depending on the nature of the pathogen. This variability is indeed intriguing but does not bear directly on our model of T-cell migration and functional responses.

Ulrich H. von Andrian, M.D., Ph.D.
Harvard Medical School, Boston, MA 02115

Charles R. Mackay, Ph.D.
Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia

3 References

1. 1

   Westermann J, Pabst R. Distribution of lymphocyte subsets and natural killer cells in the human body. Clin Investig 1992;70:539-544
   CrossRef | Medline

2. 2

   Arstila TP, Casrouge A, Baron V, Even J, Kanellopoulos J, Kourilsky P. A direct estimate of the human alphabeta T cell receptor diversity. Science 1999;286:958-961
   CrossRef | Web of Science | Medline

3. 3

   Bousso P, Casrouge A, Altman JD, et al. Individual variations in the murine T cell response to a specific peptide reflect variability in naive repertoires. Immunity 1998;9:169-178
   CrossRef | Web of Science | Medline